Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs likely a result of many variants each contributing modestly to risk. Genetic studies in animal models and humans have to date made slow progress in identifying genes individual risk variants. However, modern high-throughput approaches such as genome-wide association studies or genomic expression profiling promise to rapidly increase the pool of potential candidate genes influencing AUDs. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design to focus on both gene discovery and functional interpretation for the genetics of AUDs. This application is the outgrowth of a P20 Developmental Center grant that established the VCU Alcohol Research Center in 2009. Having made significant progress, we propose here to extend and enlarge that Center. Our approach includes three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes, rather than single genes; 2) A cross-species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; 3) A highly integrative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists or networks for further experimental validation in the component projects. We request five years of support for six research projects and pilot grants for genetic studies in mice, worms, flies, and humans. Three projects will be in human genetics with a novel clinical laboratory component for assessing targeted genetic influences on human behavioral responses to ethanol in a controlled environment. All projects will be supported by an Administrative Core, an Analytic and Informatics Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores are clearly greater than the sum of their parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to become a national resource making major contributions to the advancement of our understanding of the etiology of AUDs and their prevention and treatment.